Characterizing the molecular pathways used by HIV-1 during virus infection is important to understanding both the pathogenesis of HIV and to evaluating and developing new therapies and vaccines for AIDS. We have been studying the early molecular events involved in HIV-1 cell attachment and infection of human cells. We are investigating: 1) the role of cell surface heparan sulfate proteoglycans in T cell tropic HIV binding and cell penetration, and 2) the molecular events mediating primary/monocytotropic virus entry.1. Role of cell surface proteoglycans in HIV infection. Following initial HIV binding to the CD4 receptor, the virus envelope is thought to bind to other cell surface molecules during the attachment and fusion process. We have observed that heparan sulfate proteoglycan(HS) mediates some the second steps in virus entry by interacting with an oligomeric form of envelope gp120 through a specific subregion of the the V3 region or "principal neutralizing domain". This interaction controls the kinetics of virus entry and is critical for rapid virus entry and infection. Regulation of HS synthesis is important for determining the extent of virus entry through this pathway. Our results also indicate that other molecules interact with the V3 region in close approximation to the HS binding site. 2. Identification of co-receptors for HIV. We are characterizing cell surface molecules which are required for infection of primary and T-cell tropic HIV isolates. We have generated monoclonal antibodies to cells competent to growth primary viruses and are screening these antibodies for HIV blocking activity. MAbs which specifically react with HIV binding structures will be biochemically and functionally characterized. Genetic approaches are being developed to clone genes encoding molecules which mediate primary HIV infection. Identifying the molecular targets of HIV infection is important to understanding and developing new therapeutics and vaccines for AIDS.